Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model.
Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model.
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DOI：
10.1038/srep30038
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发表时间：
2016-07-22
影响因子：
4.6
通讯作者：
Vargesson N
中科院分区：
文献类型：
--
作者：
Beedie SL;Mahony C;Walker HM;Chau CH;Figg WD;Vargesson N
血管生成，即新血管的形成，对肿瘤的生长、稳定和发展至关重要。血管生成抑制剂现已广泛应用于临床；然而，关于其致畸作用机制的研究相对较少。为了解决这一问题，我们在发育中的斑马鱼和鸡胚胎模型中筛选了多种血管生成抑制剂，以评估其发育缺陷和潜在的致畸作用。我们证实了先前的报道，舒尼替尼、索拉非尼和TNP-470是致畸的，并证明阿西替尼、帕唑帕尼、万德替尼和依维莫司在这些模型中也是致畸的。剂量反应研究发现，药物在体外抑制HUVEC细胞增殖，并在体内靶向胚胎发育中的血管。这进一步证明了在临床环境中使用这些药物存在胎儿毒性的潜在风险，并强调了胚胎血管发育和维持的重要性。我们得出结论，血管生成抑制剂，无论分子靶点，是致畸时暴露于鸡胚胎。
Angiogenesis, the formation of new blood vessels, is essential for tumor growth, stabilization and progression. Angiogenesis inhibitors are now widely used in the clinic; however, there are relatively few published studies on the mechanism of their presumed teratogenic effects. To address this issue, we screened a variety of angiogenesis inhibitors in developing zebrafish and chicken embryo models to assess for developmental defects and potential teratogenic effects. We confirmed previous reports that sunitinib, sorafenib and TNP-470 are teratogenic and demonstrate that axitinib, pazopanib, vandetanib, and everolimus are also teratogens in these models. A dose response study identified the drugs inhibit HUVEC cell proliferation in vitro, and also target the developing blood vessels of embryos in vivo. This provides further evidence for the potential risk of fetal toxicity when using these drugs in a clinical setting, and emphasizes the importance of the development and maintenance of the vasculature in the embryo. We conclude that angiogenesis inhibitors, regardless of the molecular target, are teratogenic when exposed to chicken embryos.